Sodium [[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]ac etate (hereinafter referred to as Compound (I) or Active Ingredient in this specification) is a useful compound as an inhibitor against human non-pancreatic secretory phospholipase A2 (hereinafter referred to as sPLA2), as disclosed in JP-A 7-285933, European Patent Application No. 95302166.4 (EP Publ. No. 0 675 110 A1) and U.S. Pat. No. 5,654,326; the disclosures of which are incorporated herein by reference.
Medicaments for injections are usually formulated into not only emulsions, suspensions or solutions, but also lyophilized preparations to be dissolved before use which are stable, can be preserved and are easily reconstituted. As is generally known to those skilled in the art, it is easy to keep the lyophilized preparations sterile and eliminate foreign insoluble matter from the lyophilized preparations.
Concerning injectable preparations, JP-A 7-285933 discloses an isotonic saline solution of Compound (I) at a concentration of 0.1 g/L and a method to intravenously infuse the saline solution but does not disclose any compositions like those of the present invention. A stable pharmaceutical preparation of Compound (I), in particular, a stable injectable preparation of Compound (I) or a lyophilized preparation of Compound (I) for preparing injectable preparations has long been desired.
Storage of a pharmaceutical composition of Compound (I) prepared by known methods may lead to degradation of its content and a coloring and a worsening of its reconstitution properties, especially in the case of injections to be dissolved before use. It is difficult to provide a pharmaceutical composition of Compound (I) which has good stability and a good reconstitution property, especially for injections of Compound (I) to be dissolved before use, after long storage at room temperature. In more detail, as Compound (I) is a sparingly soluble compound, it is difficult to obtain a clear solution of Compound (I) by only mixing the Compound (I) with a solvent, which makes it desirable to obtain an injection solution and a processing solution.
Even if a clear solution of Compound (I) were obtained by changing conditions such as temperature and the like, degradation of a solution of Compound (I) and a clouding would occur after long storage, resulting in degradation and non-uniform contents of Compound (I) in the solution or the lyophilized injectable preparation of Compound (I). One of the problems to be solved by the present invention is to keep Compound (I) stable in aqueous carriers.
Preparing lyophilized products by the methods of the prior art sometimes causes problems in quality. These problems include a sublimation of some ingredients coinciding with that of water, content of ingredients decreases in the lyophilized product, a partial solidifying of product, lyophilized preparations are cracked and shrunk and may have a thin layer on the top of the cake, adherence to the upper portion of vials and spatters, and non-uniform appearance of lyophilized cakes. Pharmacists and the like require injections to be dissolved in an infusion solution before use, for example, a lyophilized injection should have good reconstitution properties.
Another problem to be solved by the present invention is to provide an excellent lyophilized preparation of Compound (I) of good quality with a uniform appearance, good reconstitution and no degradation of its contents during storage.